Functionalized Analogues of an Unnatural Amino Acid that Mimics a Tripeptide β-Strand

Abstract

This paper introduces polar and hydrophobic variants of the unnatural amino acid Hao, which mimics the hydrogen-bonding functionality of one edge of a β-strand. In these variants, the methyl side chain of Hao is replaced with acidic, basic, and hydrophobic groups. These modifications can impart improved solubility and additional side-chain interactions to peptides containing Hao.Peptidomimetic templates that mimic or induce helix, turn, or β-sheet structures are useful for studying and controlling the conformations and interactions of peptides and proteins. 1 Our research group previously introduced the unnatural amino acid Hao as a tripeptide β-strand mimic that forms hydrogen bonds from only one edge (Figure 1). 2 We have developed Haocontaining peptides that fold to form β-sheet structure, dimerize through edge-to-edge β-sheet interaction, and antagonize β-sheet aggregation. 3 Other research groups have investigated Hao and related structures in peptidomimetic compounds and hydrogen-bonded assemblies. 4,5The original unnatural amino acid Hao provides the hydrogen-bonding functionality of the peptide main chain but lacks side-chain functionality. In this paper, we introduce variants of Hao with acidic, basic, and hydrophobic side chains: Hao K , Hao D , Hao F , and Hao L (Figure 1). We have developed these variants to address specific problems with solubility and folding of Hao-containing peptides that we have encountered in our own research, and we anticipate that these variants and types of side chains will be useful to others. 6,7 jsnowick@uci.edu. (Figure 2). 8 NIH Public AccessThe syntheses of Hao analogues 1a-1d are similar to the synthesis of Fmoc*-Hao-OH that we reported previously but require an alkylation reaction to introduce the different side chains and tactical changes to tolerate the functional groups and protecting groups of the side chains. The syntheses of 1a-1d begin with ethyl or allyl 5-nitrosalicylate and involve alkylation of the phenol group to introduce the side chains, conversion of the ester group to the hydrazide, and conversion of the nitro group to the oxamic acid. 9Alkylation of ethyl 5-nitrosalicylate with Boc-protected 3-amino-1-bromopropane, 10 t-butyl bromoacetate, benzyl bromide, or isopentyl bromide gives ethers 2a-2d (Scheme 1). Alkylation to form 2a and 2c proceed smoothly at 70-100 °C. For 2b, the temperature must be kept below 50 °C to minimize undesired reactions. For 2d, sodium iodide is added to increase the rate of alkylation. Saponification of the ethyl ester groups of 2a-2d is sluggish at room temperature but occurs in 2-5 h upon heating at reflux in aqueous THF (Scheme 1). Carboxylic acids 3a, 3c, and 3d are readily isolated by neutralization with strongly acidic ion exchange resin (Amberlite IR-120) and removal of THF. Competing reactions during the hydrolysis of 2b are a problem. To circumvent this problem, we selected the orthogonal allyl protecting group and have used allyl 5-nitrosalicylate to prepare acid 3b. Alkylation of allyl 5-nitrosalicylate w...

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